Abstract
Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson's disease (PD). Previously, we reported the structure of alpha-synuclein fibrils (residues 1-121), composed of two protofibrils that are connected via a densely-packed interface formed by residues 50-57 (Guerrero-Ferreira, eLife 218;7:e36402). We here report two new polymorphic atomic structures of alpha-synuclein fibrils termed polymorphs 2a and 2b, at 3.0 Å and 3.4 Å resolution, respectively. These polymorphs show a radically different structure compared to previously reported polymorphs. The new structures have a 10 nm fibril diameter and are composed of two protofilaments which interact via intermolecular salt-bridges between amino acids K45, E57 (polymorph 2a) or E46 (polymorph 2b). The non-amyloid component (NAC) region of alpha-synuclein is fully buried by previously non-described interactions with the N-terminus. A hydrophobic cleft, the location of familial PD mutation sites, and the nature of the protofilament interface now invite to formulate hypotheses about fibril formation, growth and stability.
Highlights
Lewy bodies (LB) and Lewy neurites (LN) are neuropathological hallmarks of Parkinson’s disease and other Lewy body disorders
The maps show clear side-chain densities and ß-strand separation along the helical axis, and indicate that both fibril types are formed by two protofilaments of approximately 5 nm diameter, which are composed of distinct rungs of density
We present here two new structures of a-Syn fibril polymorphs (polymorph 2a (PDB ID 6rt0), and polymorph 2b (PDB ID 2rtb))
Summary
Lewy bodies (LB) and Lewy neurites (LN) are neuropathological hallmarks of Parkinson’s disease and other Lewy body disorders. Our recent work on the structure of recombinant a-Syn(1-121), using cryo-electron microscopy (cryo-EM) (Guerrero-Ferreira et al, 2018) and other investigations on full-length a-Syn (Li et al, 2018a; Li et al, 2018b) revealed a-Syn fibrils in a structure composed of two protofilaments that buried the sites associated with familial PD in the interface region between the two protofilaments. This is here termed a-Syn polymorph 1a. Our structures reveal remarkable differences to the previously solved a-Syn polymorphs, and inform new hypotheses to explain the mechanism of and factors involved in in vitro amyloid fibril assembly, the potential role of familial PD mutations on fibril structure, and contribute to our understanding of amyloid fibril polymorphism
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